The present invention relates broadly to the formation of agglomerates, to particulate solid carriers, and/or binders, and/or pharmaceutically active materials for use in the formation of agglomerates, and to methods of forming same and agglomerates so produced. More specifically, the present invention relates to the field of pharmaceutical dosage form design and, in particular, the production of unique solid carriers and/or pharmaceutically active materials and agglomerated dosage forms for administration of pharmaceutically active materials to patients.
There are several known methods of treating diseases and conditions of the upper and lower airway passages and the lungs. These conditions include, for example, asthma and rhinitis. One such technique involves administering certain pharmacologically active agents or drugs such as, for example, mometasone furoate, topically to the airway passages or lungs in an immediately useable form. Mometasone furoate is a topically effective, steroidal anti-inflammatory.
Oral inhalation therapy is one method of delivering such topically active drugs. This form of drug delivery involves the oral administration of a dry powdered drug directly to the afflicted area in a form which is readily available for immediate benefit.
However, inhalation therapy is a particularly demanding dosing system and it involves its own set of unique design and performance problems. Among those problems is a concern over the accuracy and repeatability of dosing. One must try to ensure that the same amount of drug is administered each and every time. Moreover, unlike pills, capsules and creams, oral inhalation therapy must concern itself with not only the dosage form itself, but also a drug delivery device and the interaction between them. One has only to consider over-the-counter nasal sprays to understand this problem. When one squeezes a conventional spray bottle, it is difficult to apply the same amount of force each and every time. With even a slight difference in force, differences in the amount of drug administered can result. Even with somewhat more consistent pump style spray applicators, variations in dosing can occur. While such variation is usually not a problem when administering OTC nasal sprays, variation should be minimized where possible when administering potent prescription medications for such serious conditions as asthma. The dangers of over-medicating or under-medicating and the consequences of such unwanted deviation can be profound. The problem becomes even more complex when the size of the doses are as small as they often are in oral inhalation therapy.
To help mitigate these problems, companies such as Schering Corporation have developed complex and highly accurate inhaler systems for administering powdered medications such as those described in PCT International Publication WO 94/14492, the text of which is hereby incorporated by reference. Such inhaler systems were designed to meter out an exact dose of a powdered medication using a dosing hole of a specific size. The hole is completely filled with drug prior to administration and the entire contents of the dosing hole are then delivered to the patient through a nozzle. The dosing hole is then filled again for the next dose. These devices have been specifically designed to remove, as much as possible, human error and mechanically induced variability in dosing.
While such devices represent a significant advance in oral inhalation therapy, there are still some circumstances in which problems may remain. These problems often center on the properties of the pharmacologically active agent and their interaction with the inhaler. For example, certain drugs are not xe2x80x9cfree-flowingxe2x80x9d and that may make it difficult to move the drug from storage in a reservoir, to measurement in a dosing hole, to delivery from the inhaler. Other drugs may suffer from electrostatic charge problems or may exhibit an unacceptable degree of cohesive force. Such drugs may be xe2x80x9csticky,xe2x80x9d even when in powdered form. These drugs may clog the inhaler/applicator, affecting its ability to properly meter the intended amount of medication. Such powders may also adhere to the nozzle of the applicator, thus reducing the amount of medication actually delivered. This is often referred to as xe2x80x9chang up.xe2x80x9d Drugs may also be xe2x80x9cfluffyxe2x80x9d which makes handling and loading sufficient drug into a dosing hole a real challenge. To make matters even worse, these and other physical properties of various pharmacologically active agents may vary within a single batch of material. This can defeat attempts to compensate.
Related problems may also result based upon the small size of the particles which are generally used in inhalation therapy. Inhalation therapy commonly involves drug particles which are on the order of 10 microns or below. This ensures adequate penetration of the medicament into the lungs of the patient as well as good topical coverage. In order to provide adequate dispensing of such medicines, tight control must be maintained on the size of the particles of the drug. However, powders of this size can be extremely difficult to work with, particularly when small dosages are required. Such powders are typically not free-flowing and are usually light, dusty or fluffy in character, creating problems during handling, processing, and storing. In addition, it can be difficult to repeatedly and accurately load such materials into the dosing hole of an inhaler. Thus not only the properties of the drug, but also the required size of the therapeutic particulate, can combine to cause considerable problems in terms of handling and dosing.
One method of improving the ability to administer fine powdered medicaments is by the inclusion of dry excipients such as, for example, powdered lactose. However, it has been determined that when particularly small doses of medication are required, such as under about 100-500 xcexcg of drug, the inclusion of conventional excipients may not adequately compensate for the problems associated with the use of fine drug particles. In addition, dry excipients as commonly used generally have particle sizes which are significantly larger than the particle size of the drug. Unfortunately, the use of such large particles can have a significant impact on the amount of drug delivered from dose to dose. Moreover, the intended benefits of the use of such excipients begins to diminish as the size of the dose decreases. Therefore, particle retention within the metering device or the inhalation nozzle and other handling issues can become a serious problem.
Alternatively, drug products can be processed to form agglomerates or pellets which are generally more free-flowing and bulky. One method of agglomerating drugs is described in PCT International Publication WO 95/09616.
As described therein, agglomerates of finely divided powder medicaments, such as micronized powders having a particle size smaller than 10 xcexcm, can be produced which require no binders. However, they can be formed with excipients. These agglomerates can then be administered through an inhaler for powdered medications.
The ability to create particles without an added binder is significant to inhalation therapy and can pose a great advantage over other techniques which use water or other traditional binders in agglomerate formation. Agglomerates of pure drug can provide great advantages when formulating and handling powders. It has been found, however, that at doses of about 100-500 xcexcg of a drug such as mometasone furoate and below, agglomerates of pure drug can suffer from hang up and dosing variability can be a genuine concern. Even in dosing systems designed to provide relatively larger doses of pharmacologically active agent, such as over 500 xcexcg, the resulting agglomerates of pure drug can still suffer from integrity problems. These agglomerates are still relatively soft and can be crushed during metering thereby providing variability in dosing. The material can also be broken fairly readily by, for example, dropping an inhaler from a height of about four feet. This would prematurely result in the formation of smaller particles which are more difficult to handle. In fact, it is the handling difficulties of the fine drug particles that originally necessitated agglomeration.
If binder-containing agglomerates are to be used, such agglomerates can be made by the methods described in, for example, U.S. Pat. No. 4,161,516 and Great Britain Patent 1,520,247 which disclose the use of certain binding materials, including water, for the production of agglomerates for oral inhalation. According to the processes described therein, prior to agglomeration, the moisture content of certain xe2x80x9cself agglomeratingxe2x80x9d or hygroscopic micronized drugs are elevated. After the micronized powder has been elevated to the desired water content level, it is agglomerated. Non-hygroscopic materials must be bound with more traditional binders as described therein. Similarly, PCT International Publication WO 95/05805 discloses a process for forming agglomerates where a mixture of homogeneous micronized materials is treated with water vapor to eliminate any convertible amorphous content which may destabilize at a later point. After treatment with water vapor, the now crystalline material is agglomerated. However, this application warns that if the vapor exposure is conducted after agglomeration, the product is xe2x80x9cuseless in an inhalation device.xe2x80x9d
The effect of moisture on the tableting characteristics of anhydrous lactose is discussed in Sebhatu, Elamin and Ahineck, xe2x80x9cEffect of Moisture Sorption on Tableting Characteristics and Spray Dried (15% Amorphous) Lactose,xe2x80x9d Pharmaceutics Research, Vol. 11, No. 9, pp. 1233-1238 (1994). The article does not, however, discuss the formation of agglomerates, or the production of agglomerates which can yield an acceptable xe2x80x9cfine particle fraction,xe2x80x9d also known as a xe2x80x9crespirable fractionxe2x80x9d when administered as part of oral inhalation therapy.
One particularly important approach to agglomerate formation was disclosed in PCT International Publication WO 98/41193. The invention described therein included a process of producing agglomerates. The process included the steps of providing particles of at least one first material, generally a pharmacologically active agent, and providing particles of at least one solid binder or solid carrier. At least one of these two particles, the drug or the solid binder, included convertible amorphous content. The convertible amorphous content of the binder and/or the drug should be capable of being converted to a crystalline form upon exposure to a pre-selected stimulus which includes, among other things, humidity.
The particles of binder or carrier and drug are then agglomerated while maintaining the convertible amorphous content. After agglomeration is complete, the convertible amorphous content within the agglomerates is exposed to the pre-selected stimulus and is converted to a crystalline form.
Not surprisingly it is very important to the performance of the agglomerates and to the ability to deliver an acceptable fine particle fraction of free particles of the pharmaceutically active materials that the properties of the agglomerate carrier or binder be tightly controlled. It is also important to control the properties of the drug particles. Desirably one would be able to provide not only particles of a specified size, but also a very tight particle size distribution. Ideally, one could coordinately provide a desirable amount of convertible amorphous content. The amorphous content can be critical to the strength, bulk density and/or hardness of the resulting agglomerate. If too little amorphous content is present, then the agglomerates will be insufficiently robust to withstand packaging, shipment and use. If too much amorphous content is provided, then there is a risk that the agglomerate will be too strong and/or hard and that an unacceptable fine particle fraction will be delivered from a powder inhaler. Similarly, the size of the particles and the particle size distribution are critical to accurately formulating the agglomerates to provide an acceptable fine particle fraction and to provide accurate dose delivery uniformity due to consistency of the resulting bulk density. Unfortunately, no processes are known for reproducibly producing particles of drugs and/or solid carriers with accurately controlled particle size distribution and amorphous content. It is to this improvement that the present invention is directed.
The present invention is directed to a method of producing a particulate substance which is particularly suitable for use in producing agglomerates containing a pharmaceutically active material and preferably a solid binder or solid carrier. The particulate produced by the process is also contemplated. The method includes the steps of micronizing a particulate material from an original particle size to an intermediate particle size in a manner which imparts an increase in the amount of amorphous content of the particulate. Some or all of that imparted amorphous content is convertible amorphous content. The particle size distribution is reduced by this micronizing step. Thereafter, the micronized particulate is xe2x80x9ccuredxe2x80x9d by exposure to a pre-determined stimulus such as, for example, exposure to controlled relative humidity at a specified temperature. This curing process is conducted for a time sufficient to reduce at least a portion, and in many instances preferably all, of the amorphous content of the particulate which is convertible when exposed to that particular stimulus. Thereafter, the cured particulate is micronized again wherein the particulate is reduced further in size from the intermediate particulate size to a final particulate size. A desired level of convertible amorphous content is also created by the subsequent micronizing step.
The particulate can be any pharmaceutically acceptable material including a pharmaceutically active material (i.e., a drug) or a non-therapeutically active material such as a solid carrier, solid binder or other pharmaceutical excipient. Indeed, particulate can be composed of both at the same time.
Stated another way, the method of producing a particulate in accordance with the present invention includes the steps of micronizing a particulate material having a first particle size distribution, from that first particle size distribution to intermediate particles having a second particle size distribution. The second particle size distribution is different than the first particle size distribution as the particulate has been made smaller, on average. Micronization is accomplished in a manner which imparts an increase in the amorphous content of the intermediate particulate relative to the starting particulate before the preceding micronization step. The intermediate particulate is then cured to reduce its amorphous content. Finally, the cured intermediate particulate is re-micronized to a third particle size distribution, which is different than the first or second particle size distribution because the particles are again made smaller on average. The re-micronized particulate also have an amount of amorphous content which is greater than that of the cured intermediate particulate. Thus, in a first micronizing step, an amount of amorphous content is imparted to the particles. Curing will reduce an amount of amorphous content which is convertible when exposed to the stimulus. This also reduces the total amorphous content. Thereafter, upon re-micronizing, the particles contain additional amorphous content, preferably convertible amorphous content.
Preferably, the final particle size of particulate solid carrier produced in accordance with this process is at least about 60% by volume less than or equal to 5 xcexcm and its pre-determined convertible amorphous content (as determined by specific heat of crystallization, using techniques described infra) is between about 1 and about 20 Joules/gram (xe2x80x9cJ/gxe2x80x9d or xe2x80x9cJ/gramxe2x80x9d). More preferably, the final particle size of the particulate solid carrier is at least about 70% by volume less than or equal to 5 xcexcm and a pre-determined convertible amorphous content is between about 2 and about 16 Joules/gram. Most preferably, the final particle size of the particulate solid carrier is at least about 80% by volume less than or equal to 5 xcexcm and the pre-determined amorphous content is between about 3.8 and about 7 Joules/gram.
Preferably, the final particle size of particulate pharmaceutically active material produced in accordance with these methods is at least about 60% by volume less than or equal to 5 microns and a pre-determined convertible amorphous content is between about 1 and about 20 Joules/gram. More preferably, the final particle size of the particulate pharmaceutically active material is at least about 80% by volume less than or equal to 5 microns and a pre-determined convertible amorphous content is between about 2 and about 16 Joules/gram. Most preferably, the final particle size of the particulate pharmaceutically active material is at least about 90% by volume less than or equal to 5 microns.
Preferably, when the pharmaceutically acceptable material useful for the formation of an agglomerate treated by these processes is a non-therapeutically active, non-pharmaceutically active material, the pharmaceutically acceptable material can be a common additive or excipient such as lactose (including both hydrous and anhydrous lactose), and the like. However, since the same process can be performed on the pharmaceutically active material as well, the pharmaceutically active material can be agglomerated with either a traditional solid carrier or a solid carrier which has also been produced in accordance with the methods of the present invention. The pharmaceutically active material produced using these methods will have both controlled particle size distribution and controlled amorphous content and can also be used to form agglomerates without an additional solid carrier and/or with another pharmaceutically active agent, one treated by this method or otherwise.
The present invention also relates to an agglomerate produced by agglomerating a pharmaceutically active substance and/or solid carrier particles at least one of which has been produced in accordance with the present invention.